Process

ABSTRACT

This invention relates to cucurbituril and/or one or more derivatives thereof with low formaldehyde content, to a process of manufacturing said cucurbituril and/or one or more derivatives thereof and to the use of said cucurbituril and/or one or more derivatives thereof, in particular in consumer and industrial products, and in industrial processes.

FIELD OF THE INVENTION

This invention relates to cucurbituril and/or one or more derivativesthereof with low formaldehyde content, to a process of manufacturingsaid cucurbituril and/or one or more derivatives thereof and to the useof said cucurbituril and/or one or more derivatives thereof, inparticular in consumer and industrial products, and in industrialprocesses.

BACKGROUND OF THE INVENTION

Cucurbiturils are known to bind a number of substances to formhost-guest compounds and, for this reason, have high applicationpotential in a number of applications.

According to the state of the art, the production of cucurbiturils is achemical process, involving the polycondensation of glycoluril andformaldehyde under strongly acidic aqueous conditions at hightemperatures. For example 9 M sulphuric acid or 5 M to 9 M hydrochloricacid is used as the reaction medium and the reaction temperature ishigher than 75° C., usually between 75 and 90° C. The reaction time istypically in the order of 24 hours. Such a process is also described inU.S. Pat. No. 6 793 839.

A principal disadvantage of this process is the presence of unreactedformaldehyde in the product.

The regulatory constraints on formaldehyde are continuously increasingowing to the carcinogenic potential of this substance. Decreasing thelevel of residual formaldehyde in consumer products is therefore arecognised necessity. For example, natural formaldehyde levels as low asthose measured in plant material such as fruits and vegetables (6 to 35ppm) are highly desirable (EFSA Journal 2014;12(2):3550).

Therefore, a process leading to the formation of cucurbiturils and/orone or more derivatives thereof with low residual formaldehyde levels,is highly desirable.

SUMMARY OF THE INVENTION

In a first aspect of the present invention, there is providedcurcubituril and/or one or more derivatives thereof comprising less than300 ppm formaldehyde, that is to say, provided is cucurbituril and/orone or more derivatives thereof with a residual formaldehyde level ofless than 300 ppm. The cucurbituril and/or one or more derivativesthereof may comprise less than 200 ppm, less than 100 ppm, less than 50ppm formaldehyde. Preferably, the cucurbituril and/or one or morederivatives thereof comprises less than 25 ppm formaldehyde. Morepreferably, the cucurbituril and/or ore or more derivatives thereofcomprises less than 10 ppm formaldehyde. Low levels of residualformaldehyde are advantageous for applications in pharmaceutical,personal care, household, industrial and consumer products.

In a second aspect of the invention, there is provided a process for thepreparation of cucurbituril and/or one or more derivatives thereofcomprising mixing glycoluril or a derivative thereof with a methylenebridging agent, in the presence of an acid, and in the absence of anyformaldehyde or formaldehyde precursor. In particular, the methylenebridging agent is a dialkoxymethane reagent.

The glycoluril is selected from the group consisting of unsubstitutedglycoluril, alkoxy methylated glycoluril, other derivatives thereof, anda mixture thereof.

In a third aspect of the invention, there is provided a process for thepreparation of cucurbituril and/or one or more derivatives thereofcomprising mixing a fully alkoxy methylated glycoluril withunsubstituted glycoluril in the presence of an acid, and in the absenceof any formaldehyde or a formaldehyde precursor.

In one embodiment, the fully alkoxy methylated glycoluril istetramethoxymethylglycoluril.

In one embodiment, the acid used in the second and third aspects is amineral acid or an organic acid. The acid may be selected from sulfuricacid, nitric acid, hydrochloric acid, hydrobromic acid, hydroiodic acid,phosphoric acid, toluenesulfonic acid and methanesulfonic acid.

In one embodiment, the acid is methanesulfonic acid.

In a fourth aspect of the invention, there is provided cucurbituriland/or one or more derivatives thereof obtained or obtainable by theprocess described in the second or third aspects of the invention.

In a fifth aspect of the invention, there is provided a compositioncomprising cucurbituril and/or one or more derivatives thereofcomprising less than 300 ppm formaldehyde and a suitable carrier.

In a sixth aspect of the invention, there is provided use ofcucurbituril and/or one or more derivatives thereof described in thefirst or fourth aspect in consumer or industrial products.

DETAILED DESCRIPTION OF THE INVENTION

The present inventors have found a process for preparing cucurbiturilsand/or one or more derivatives thereof without adding any formaldehydeor formaldehyde precursor as starting reagent. The cucurbituriis and/orone or more derivatives thereof obtained by this process areparticularly clean and free of residual formaldehyde. Advantageously,the formaldehyde free cucurbituril and/or one or more derivativesthereof is obtained without the need for the onerous purification stepsoften required with the prior art methods.

Cucurbituril The present invention provides formaldehyde freecucurbituril and/or one or more derivatives thereof.

Cucurbituril is a member of the cavitand family, and the generalcucurbituril structure is based on the cyclic arrangement of glycolurilsubunits linked by methylene bridges.

For example, cucurbit[8]uril (CB[8]; CAS 259886-51-6) is a barrel shapedcontainer molecule which has eight repeat glycoluril units and aninternal cavity volume of 479A³ (see structure below).

In one embodiment, the cucurbituril is a CB[5], CB[6], CB[7], CB[8],CB[9], CB[10], CB[11], CB[12], CB[13] or CB[14] compound.

In one embodiment, the cucurbituril is a CB[5], CB[6], CB[7], CB[8],CB[9], CB[10], CB[11] or CB[12] compound.

In one embodiment, the cucurbituril is a CB[5], CB[6], CB[7], or CB[8]compound.

In one embodiment, the cucurbituril is a CB[6] compound.

In one embodiment, the cucurbituril is a CB[7] compound.

In one embodiment, the cucurbituril is a CB[8] compound.

The cucurbituril of the invention may include a single analogue ofcucurbituril, or may alternatively include two or more different sizedcucurbiturils selected from the group consisting of CB[5], CB[6], CB[7],CB[8], CB[9], CB[10], CB[11], CB[12], CB[13] and CB[14]. A mixture oftwo or more different cucurbiturils is defined as CB[n].

In one embodiment, the cucurbituril is a CB[n] mixture.

When the cucurbituril of the invention comprises at least two differentcucurbiturils selected from CB[5], CB[6], CB[7] and CB[8], the totalconcentration of the CB[5], CB[6], CB[7] and/or CB[8] may be greaterthan 75% by weight, more particularly greater than about 90% by weight,more particularly greater than about 99% by weight of the total weightof cucurbituril. The remaining components of the cucurbituril maycontain CB[4], CB[9] and/or higher cucurbiturils (i.e. CB[10]-CB[20]),either as a single sized cucurbituril or as a mixture of these sizes.

The % weights of cucurbiturils described above are based on the totalweight of cucurbituril (of all sizes).

Cucurbituril derivatives are provided and find use in the compositionsand applications described herein. A derivative of a cucurbituril is astructure having one, two, three, four or more substituted glycolurilunits. A substituted cucurbituril compound may be represented by thestructure below:

wherein:

n is an integer between 4 and 20;

and for each glycoluril unit:

each X is O, S or NR³, and

—R¹ and —R² are each independently selected from —H and the followingoptionally substituted groups: —R³, —OH, —OR³, —COOH, —COOR³, —NH₂,—NHR³ and —N(R³)₂ where —R³ is independently selected from C₁₋₂₀alkylgroup, C₆₋₂₀carboaryl group, and C₅₋₂₀heteroaryl group, or where —R¹and/or —R² is —N(R³)₂, both —R³ together form a C₅₋₇ heterocyclic ring;or together —R¹ and —R² are C₄₋₆alkylene forming a C₆₋₈carbocyclic ringtogether with the uracil frame.

In one embodiment, one of the glycoluril units is a substitutedglycoluril unit. Thus, —R¹ and —R² are each independently —H for n−1 ofthe glycoluril units,

In one embodiment, n is 5, 6, 7, 8, 9, 10, 11 or 12.

In one embodiment, n is 5, 6, 7 or 8.

In one embodiment, each X is O.

In one embodimeht, each X is S.

In one embodiment, R¹ and R² are each independently H.

In one embodiment, for each unit one of R¹ and R² is H and the other isindependently selected from —H and the following optionally substitutedgroups: —R³, —OH, —OR³, —COOH, —COOR³, —NH₂, —NHR³ and —N(R³)₂. In oneembodiment, for one unit one of R¹ and R² is H and the other isindependently selected from —H and the following optionally substitutedgroups: —R³, —OH, —OR³, —COOH, —COOR³, —NH₂, —NHR³ and —N(R³)₂. In thisembodiment, the remaining glycoluril units are such that R¹ and R² areeach independently H.

Preferably —R³ is C₁₋₂₀alkyl group, most preferably C₁₋₆alkyl group. TheC₁₋₂₀alkyl group may be linear and/or saturated. Each group —R³ may beindependently unsubstituted or substituted. Preferred substituents areselected from: —R⁴, —OH, —OR⁴, —SH, —SR⁴, —COOH, —COOR⁴, —NH₂, —NHR⁴ and—N(R⁴)₂, wherein —R⁴ is selected from C₁₋₂₀alkyl group, C₆₋₂₀carboarylgroup, and C₅₋₂₀heteroaryl group. The substituents may be independentlyselected from —COOH and —COOR⁴.

In some embodiments, —R⁴ is not the same as —R³. In some embodiments,—R⁴ is preferably unsubstituted.

Where —R¹ and/or —R² is —OR³, —NHR³ or —N(R³)₂, then —R³ is preferablyC₁₋₆alkyl. In some embodiments, —R³ is substituted with a substituent—OR⁴, —NHR⁴ or —N(R⁴)₂. Each —R⁴ is C₁₋₆alkyl and is itself preferablysubstituted.

The cucurbiturils of the invention may be in the native form or they maybe modified as described above in order to improve solubility orsuspendability, and more generally their formulation and handling.

The cucurbituril and/or one or more derivatives thereof of the presentinvention are characterised by low levels of residual formaldehyde.

In one embodiment, the cucurbituril and/or one or more derivativesthereof comprises less than 300 ppm formaldehyde, that is to say, theweight ratio of formaldehyde to cucurbituril and/or one or morederivatives thereof is 300:1 000 000 or 3:10 000, more particularly,less than 200 ppm formaldehyde, even more particularly less than 100 ppmformaldehyde, for example less than 50 ppm formaldehyde, preferably lessthan 25 ppm formaldehyde.

In one embodiment, the cucurbituril and/or one or more derivativesthereof is free of formaldehyde. As used herein, the term “free offormaldehyde” or “formaldehyde free” is intended to mean cucurbiturilwith levels of formaldehyde which are equivalent to those found innature, i.e. with less than 25 ppm of formaldehyde, more particularlyless than 10 ppm of formaldehyde.

Suitable methods for measuring the level of formaldehyde in cucurbituriland/or one or more derivatives thereof will be known to those skilled inthe art. The level of residual formaldehyde in samples can be determinedusing HPLC with fluorescence detection. Post column derivatisation offree formaldehyde is done using Nash reagent in a compartment of theHPLC system by automatic pump. The derivatisation is done inline,therefore all portions eluting from the column will react. Fluorescenceis then used to measure the quantity of formaldehyde in the sample.

Process

The cucurbituril and/or one or more derivatives thereofwith lowformaldehyde content may be prepared by mixing unsubstituted glycoluriland/or a derivative thereof with a methylene bridging agent, in thepresence of an acid.

The terms “methylene bridging agent” and “reagent” are usedinterchangeably throughout.

The reaction of unsubstituted glycoluril and/or a derivative thereof andthe reagent is required to take place in the presence of an acid. Theacid acts to catalyse the reaction(s) taking place. Without the acid,the unsubstituted glycoluril and/or a derivative thereof and the reagentwill not react.

Suitable acids for use in the processes described herein include strongacids. Examples of strong acids include mineral acids and organic acids,such as sulfuric acid, hydrochloric acid, hydrobromic acid, hydroiodicacid, phosphoric acid, toluenesulphonic acid, and alkanesulphonic acid.However in principle, any acid can be used.

In particular the acid used is an alkanesulphonic acid. Examples ofalkanesulphonic acids include methanesulphonic acid, ethanesulphonicacid, n-propanesulphonic acid, isopropanesulphonic acid,n-butanesulphonic acid, isobutanesulphonic acid, sec-butanesulphonicacid, tert-butanesulphonic acid, and mixtures thereof.

In one embodiment, the acid is methanesulphonic acid.

In one embodiment, the unsubstituted glycoluril and/or a derivativethereof and the acid are mixed together simultaneously. The acid may bepresent in excess which allows the unsubstituted glycoluril and/or aderivative thereof to dissolve in the acid. The reagent is then addedportion-wise or drop-wise to the unsubstituted glycoluril and/or aderivative thereof and acid mixture.

Alternative methods include simultaneous addition of the unsubstitutedglycoluril and/or a derivative thereof, the acid and reagent. Anothermethod involves the sequential addition of the unsubstituted glycoluriland/or a derivative thereof, the acid and the reagent. For example, thereagent may be added to the acid followed by the unsubstitutedglycoluril and/or a derivative thereof.

The acid may be a heterogeneous acid where the phase of the acid isdifferent to that of the reagents, Alternatively, the acid may be ahomogeneous acid where the acid and the reagents are in the same phase.

Once all the components are added, the reaction mixture is then heatedto a temperature of between 40° C. and 200° C. Alternatively, theunsubstituted glycoluril and/or a derivative thereof and the acid may bemixed in a heated reaction vessel before addition of the reagent. Theheated reaction vessel may also be at a temperature of 40° C. to 200° C.

In one embodiment, the process is carried out at a temperature of atleast 40° C., more particularly at least 80° C., still more particularlyat least 90° C. For example, the process may be carried out at atemperature from about 40° C. to about 200° C., in particular, fromabout 70° C. to about 110° C., more particularly, from about 75° C. to100° C. For example, the process may be carried out at a temperature ofabout 75° C., about 85° C. or about 100° C.

The process may be reacted for up to 24 hours. More particularly, theprocess is reacted for up to 20 hours, for example up to 18 hours.However, shorter reaction times are possible and in certain instances,the process is reacted for up to 1 hour, for example up to 45 minutes orup to 30 minutes.

After prolonged heating of the reaction mixture, the mixture may becooled, for example, to room temperature.

Finally, the processes described herein may further comprise apurification step. In one embodiment the purification step is a washingstep. Alternative purification steps include recrystallization. Washingof the reaction mixture can be done with any suitable solvent. Suchsolvents will be well known to the skilled person and examples includeacetone and methanol. Washing of the reaction mixture is often requiredin order to remove any remaining reagent and acid. However, as a resultof the cleaner reaction, the washing and drying steps in the processesof the present invention are far less onerous compared to the prior artprocesses.

Formaldehyde scavengers, such as β-dicarbonyl compounds, amides, imines,acetal formers, sulfur containing compounds, activated carbon, ammonium,organic amines, an oxidizing agent or mixtures thereof, are often usedas a purification step in prior art methods. Such methods are disclosedin US 2007/0138671, herein incorporated by reference. However, again asthe result of the cleaner reaction, the processes described hereinminimise, if not eliminate, the need for scavengers in the end product.

Depending on the glycoluril derivative used, there are instances wherethe reaction of unsubstituted glycoluril and/or a derivative thereof inthe presence of an acid can be performed in the absence of a methylenebridging reagent. For example, when the starting glycolurils are amixture of fully alkoxy methylated glycoluril and unsubstitutedglycoluril, no external methylene bridging agent (e.g. dialkoxy methanereagent) is needed.

Therefore, in a further aspect of the invention, there is provided aprocess for the preparation of cucurbituril comprising reacting a fullyalkoxy methylated glycoluril with unsubstituted glycoluril in thepresence of an acid, as described above, but in the absence of amethylene bridging agent.

In one embodiment, the fully alkoxy methylated glycoluril is1,3,4,6-tetrakis(methoxymethyl)glycoluril (CAS No. 17464-88-9), whichmay also be referred to throughout as tetramethoxymethylglycoluril(TMMG).

Importantly, the processes described herein are carried out in theabsence of any formaldehyde, or any formaldehyde producing precursor.The term “formaldehyde” refers to a compound with formula CH₂O andincludes formalin which is an aqueous solution of formaldehyde. Theterms “formaldehyde producing precursor” or “formaldehyde precursor” areused interchangeably throughout and refer to polymers and oligomers offormaldehyde which exist in equilibrium with formaldehyde in water.Examples of formaldehyde precursors include paraformaldehyde (a linearpolymer of formaldehyde) and trioxane (a cyclic trimer of formaldehyde),both of which have similar chemical properties to formaldehyde and areoften used interchangeably. Other formaldehyde precursors will be knownto the skilled person.

Advantageously, the methylene bridging agents of the present invention,for example compounds of formula (IV), do not exist in equilibrium withformaldehyde in water.

Glycoluril

Glycolurils are the monomer units that make up cucurbituril. Theglycolurils are selected from the group consisting of unsubstitutedglycoluril, alkoxy-methylated glycoluril, other derivatives thereof, anda mixture thereof.

In one embodiment, the glycoluril is represented by formula (I):

wherein R¹, R², R³ and R⁴ each independently represent hydrogen or—CH₂—O-C₁-C₄ alkyl.

When at least one of R¹, R², R³ and R⁴ is —CH₂—O-C₁-C₄ alkyl group, theglycoluril may be referred to as an alkoxy-methylated glycoluril. WhenR¹, R², R³ and R⁴ are each hydrogen, the glycoluril may be referred toas unsubstituted glycoluril.

The —C₂—O-C₁-C₄ alkyl group is preferably unsubstituted.

For a mono-alkoxy methylated glycoluril, one of the R¹, R², R³ and R⁴groups represents —CH₂—O-C₁-C₄ alkyl group whilst the remaining groupsrepresent hydrogen. For a di-alkoxy methylated glycoluril, two of theR¹, R², R³ and R⁴ groups each independently represent —C₂—O-C₁-C₄ alkylgroup whilst the remaining groups represent hydrogen. For a tri-alkoxymethylated glycoluril, three of the R¹, R², R³ and R⁴ groups eachindependently represent —CH₂-O-C₁-C₄ alkyl group whilst the remaininggroup represents hydrogen. Finally for a tetra-alkoxy methylatedglycoluril, four of the R¹, R², R³ and R⁴ groups each independentlyrepresent —CH₁₂—O-C₁-C₄ alkyl group.

In one embodiment, the alkoxy methylated glycoluril is selected frommono-alkoxy methylated, di-alkoxy methylated, tri-alkoxy methylated andtetra-alkoxy methylated glycoluril or a mixture thereof.

In one embodiment, the glycoluril is monomethoxymethyiglycoluril,dimethoxymethylglycoluril, trimethoxymethylglycoluril,tetramethoxymethylglycoluril, or a mixture thereof.

In another embodiment, R¹, R², R³ and R⁴ each represent hydrogen and theglycoluril is therefore unsubstituted glycoluril and is represented byformula (II):

The unsubstituted or monomethoxy methylated, dimethoxymethylated ortrimethoxymethylated glycoluril is reacted with a methylene bridgingreagent under the conditions described hereinabove.

In one embodiment, the glycoluril is tetramethoxymethylglycoluril(TMMG), which has the structure of formula (III):

When the glycoluril is TMMG, the reaction of TMMG with unsubstitutedglycoluril in the presence of acid can be performed in the absence of amethylene bridging reagent, as described above.

Reagent

Certain processes described herein involve the reaction of a reagentwith glycolurils. The reagent must be a compound capable of formingmethylene bridges between the glycoluril units. The reagent cannot beformaldehyde, or a formaldehyde precursor, for example, paraformaldehydeor trioxane.

One class of suitable reagents are compounds with the formula (IV):

wherein each X is independently selected from an electronegative atom;

R₁ and R₂ are each independently selected from hydrogen, anunsubstituted or substituted straight chain, branched or cyclic,saturated or unsaturated hydrocarbon radical; and R represents hydrogen.

In one embodiment, each X is selected from oxygen, nitrogen, sulphur andphosphorus.

In one embodiment, the straight chain, branched or cyclic saturated orunsaturated hydrocarbon radical is substituted with halogen, hydroxyl,cyano, oxo, nitro or C₁-C₃ alkoxy.

Examples of compounds of formula (IV) include dimethoxymethane,diethoxymethane, dipropoxymethane, dibutoxymethane,1,3-dioxacyclopentane, methylidinoglycerol, 2,4-dithiapentane,bis(phenylthio)methane, bis(dimethylphosphino)rnethane, methylenediacetate and methanediol.

In one embodiment, the reagent is selected from dialkoxymethane,diethoxymethane and dipropoxymethane.

The dialkoxymethane may be selected from dimethoxymethane,diethoxymethane, dipropoxymethane (1-(propoxymethoxy)propane),diisopropoxymethane (2-(isopropoxymethoxy)propane), dibutoxymethane(1-(butoxymethoxy)butane), di(tert -butoxy)methane(2-methyl-2-{[(2-methyl-2-propanyl)oxy]methoxy}propane), and mixturesthereof.

In one embodiment, the reagent is dimethoxymethane.

Other suitable reagents include 1,3-cycloketals.

1,3-cycloketals include 1,3-dioxolane, 1,3-dioxane, glycerol formal,1,3-dioxepane, 1,3-dioxopane, Poly(vinyl formal), and the like.

Other suitable reagents include alkoxymethyl alkane sulphonate, forexample methoxymethane methane sulphonate, methoxymethylbenzenesulphonate, methoxymethyl p-toluene sulphonate, benzyloxymethylmethanesulphonate, and the like.

Compositions

In one aspect of the invention there is provided a compositioncomprising cucurbituril and/or one or more derivatives thereof with lowlevels of residual formaldehyde.

In another aspect, a composition is provided, the composition comprisingcucurbituril and/or one or more derivatives thereof, the compositionfurther comprising no more than 300, preferably no more than 150, morepreferably no more than 50, most preferably no more than 10 ppmformaldehyde originating from the cucurbituril and/or one or morederivatives thereof, that is to say formaldehyde originating from theprocess of preparing the cucurbituril and/or one or more derivativesthereof. By way of a benchmark, apple comprises about 35 ppmformaldehyde.

A composition may be a liquid or a solid, such as powder, composition.

The composition may further comprise excipients such as preservatives,dyes, pigments, sequestrants, surfactants and antioxidants.

One advantage of a composition with low levels of residual formaldehydeoriginating from the process of preparation of cucurbituril and/or oneor more derivatives thereof is that it provides more formulation spaceto include other excipients which also have residual formaldehydewithout the overall level of formaldehyde in any finished compositionbeing such as to be a drawback. Such a composition can be a consumerproduct.

The present case also provides a method of preparing a composition, themethod comprising the step of mixing cucurbituril and/or one or morederivatives thereof with low levels of residual formaldehyde, asdescribed herein, with one or more excipients, such as those used inconsumer and industrial products, and such as those excipients discussedabove.

In a further aspect of the invention there is provided a consumer orindustrial product comprising the cucurbituril and/or one or morederivatives thereof of the present invention.

The consumer product of the invention may be a detergent, a cleansingcomposition, a shampoo, a softener, a softener sheet, a conditioner, arefresher, an air freshener, a deodorizing composition, a personaldeodorant, a carrier for a catalyst, a drug delivery device, a medicaldevice, an antiperspirant, a cosmetic product, a fine fragrance, a bodymist, a candle, a hard surface cleaner, a cleansing wipe or mop, a soap,a styling gel, a humidity absorber, an air filtration device, afinishing product, a diaper or sanitary product, and the like.

Other Preferences

Each and every compatible combination of the embodiments described aboveis explicitly disclosed herein, as if each and every combination wasindividually and explicitly recited.

Various further aspects and embodiments of the present invention will beapparent to those skilled in the art in view of the present disclosure.

“and/or” where used herein is to be taken as specific disclosure of eachof the two specified features or components with or without the other.For example “A and/or B” is to be taken as specific disclosure of eachof (I) A, (ii) B and (iii) A and B, just as if each is set outindividually herein.

Unless context dictates otherwise, the descriptions and definitions ofthe features set out above are not limited to any particular aspect orembodiment of the invention and apply equally to all aspects andembodiments which are described.

Certain aspects and embodiments of the invention will now be illustratedby way of examples 5 to 8. Examples 1 to 4 are prior art methods.

Experimental and Results

The level of residual formaldehyde in the cucurbituril samples wasdetermined by Intertek using HPLC with fluorescence detection and postcolumn derivatization. The testing method followed EU Directive82/434/EEC amendment 90/207/EEC.

Example 1 Synthesis of Cucurbit[n]urils in Hydrochloric Acid UsingParaformaldehyde

Unsubstituted glycoluril (20 g) and hydrochloric acid (37 w/v, 30 mL)were placed in a reaction flask and heated to 90° C. Paraformaldehyde(8.87 g) was added in portion-wise and the reaction mixture was thenheated to 100° C. (internal) for 18 hours. The reaction mixture wascooled and added to methanol (150 mL) to produce a beige powder whichwas analysed by ¹H NMR.

Approximate Yields by ¹H NMR (% of recovered product) cucurbit[5]uril8%, cucurbit[6]uril 44%, cucurbit[7]uril 28%, cucurbit[8]uril 18%,cucurbit[9]uril 0%, cucurbit[10]uril 0% cucurbit[11]uril 0%.

Residual formaldehyde by HPLC method was 682 ppm.

Example 2 Synthesis of Cucurbit[n]urils in Hydrochloric Acid UsingFormalin

Unsubstituted glycoluril (20 g) and hydrochloric acid (37% w/v, 30 mL)were placed in a reaction flask and heated to 90° C. Formalin (40% v/v,21 mL) was added dropwise and the reaction mixture heated to 100° C.(internal) for 18 hours. The reaction mixture was cooled and added tomethanol (150 mL) to produce a yellow powder which was analysed by ¹HNMR.

Approximate Yields by ¹NMR (% of recovered product) cucurbit[5]uril 8%,cucurbit[6]uril 38%, cucurbit[7]uril 38%, cucurbit[8]uril 11%,cucurbit[9]uril 0%, cucurbit[10]uril 0% cucurbit[11]uril 0%.

Residual formaldehyde by HPLC method was 567 ppm.

Example 3 Synthesis of Cucurbit[n]urils in Methanesulphonic Acid (MSA)Using Pareformaldehyde

Unsubstituted glycoluril (20 g) and methanesulphonic acid (neat, 82 mL)were placed in a reaction flask and heated to 90° C. Paraformaldehyde(8.45 g) was added in portion-wise and the reaction mixture was thenheated to 100° C. (internal) for 18 hours, The reaction mixture wascooled and added to methanol (410 ml) to produce a brown powder whichwas analysed by ¹H NMR.

Approximate Yields by ¹H NMR (% of recovered product) cucurbit[5]uril0%, cucurbit[6]uril 63%, cucurbit[7]uril 35%, cucurbit[8]uril 0%,cucurbit[9]uril 0%, cucurbit[10]uril 0% cucurbit[11]uril 0%.

Residual formaldehyde by HPLC method was 1621 ppm.

Example 4 Synthesis of Cucurbit[n]urils in Methanesulphonic Acid UsingFormalin

Unsubstituted glycoluril (20 g) and methanesulphonic acid (neat, 82 mL)were placed in a reaction flask and heated to 90° C. Formalin (40%, 21mL) was added in drop-wise and the reaction mixture was then heated to100° C. (internal) for 18 hours. The reaction mixture was cooled andadded to methanol (410 ml) to produce a dark beige powder which wasanalysed by ¹H NMR.

Approximate Yields by ¹H NMR (% of recovered product) cucurbit[5]uril6%, cucurbit[6]uril 48%, cucurbit[7]uril 36%, cucurbit[8]uril 8%,cucurbit[5]uril 0%, cucurbit[10]uril 0%, cucurbit[11]uril 0%.

Residual formaldehyde by HPLC method was 820 ppm.

Example 5 Synthesis of Cucurbit[n]urils in Methanesulphonic Acid UsingDimethoxymethane (Methylal)

Methanesulphonic acid (neat, 82 ml) was added to the reaction vessel. Tothis methylal (24.83 ml) was added to the reaction. Unsubstitutedglycoluril (19.94 g) was added immediately afterwards in one portion andthe reaction mixture was heated to 85° C. (internal) for 18 hours. Thereaction mixture was added to methanol (250 ml) to produce a dark browngummy paste which was analysed by ¹H NMR.

Approximate Yields by ¹H NMR (% of recovered product) cucurbit[5]uril0%, cucurbit[6]uril 65%, cucurbit[7]uril 35%, cucurbit[8]uril 0%,cucurbit[9]uril 0%, cucurbit[10]uril 0%, cucurbit[11]uril 0%.

Residual formaldehyde by HPLC method was 24 ppm.

Example 6 Synthesis of Cucurbit[n]urils in Methanesulphonic Acid UsingDiethoxymethane (Ethylal)

Unsubstituted glycoluril (19.94 g) and methane sulphonic acid (neat, 82mL) were placed in a reaction flask and heated to 80° C. Ethylal (35.21mL) was added in drop-wise and the reaction mixture was then heated to100° C (internal temp) for 18 hours. The reaction mixture was cooled andadded to acetone (410 ml) to produce a brown powder which was analysedby ¹H NMR.

Approximate Yields by ¹H NMR (% of recovered product) cucurbit[5]uril8%, cucurbit[6]uril 42%, cucurbit[7]uril 43%, cucurbit[8]uril 7%,cucurbit[9]uril 0%, cucurbit[10]uril 0%, cucurbit[11]uril 0%.

Residual formaldehyde by HPLC method was 34 ppm.

Example 7 Synthesis of Cucurbit[n]urils in Methanesulphonic Acid UsingDipropoxymethane (Propylal)

Unsubstituted glycoluril (19.94 g) and methane sulphonic acid (neat, 82mL) were placed in a reaction flask and heated to 80° C. Propylal (45mL) was added in drop-wise and the reaction mixture was then heated to100° C. (internal temp) for 18 hours. The reaction mixture was cooledand added to acetone (410 ml) to produce a beige powder which wasanalysed by ¹H NMR.

Approximate Yields by ¹H NMR (% of recovered product) cucurbit[5]uril0%, cucurbit[6]uril 58%, cucurbit[7]uril 42%, cucurbit[8]uril 0%,cucurbit[9]uril 0%, cucurbit[10]uril 0%, cucurbit[11]uril 0%.

Residual formaldehyde by HPLC method was 5 ppm.

Example 8 Synthesis of Cucurbit[n]urils in Methanesulphonic Acid UsingTetramethoxymethylglycoluril (TMMG)

Unsubstituted glycoluril (19.94 g) and methane sulphonic acid (neat, 82mL) were placed in a reaction flask and heated to 80° C. TMMG (44.66 g)was added in drop-wise and the reaction mixture was then heated to 100°C. (internal temp) for 18 hours. The reaction mixture was cooled andadded to methanol (410 nil) to produce a beige powder which was analysedby ¹H NMR.

Approximate Yields by ¹H NMR (% of recovered product) cucurbit[5]uril5%, cucurbit[6]uril 58%, cucurbit[7]uril 28%, cucurbit[8]uril 9%,cucurbit[9]uril 0%, cucurbit[10]uril 0%, cucurbit[11]uril 0%.

Residual formaldehyde by HPLC method was 293 ppm.

TABLE 1 Summary of Results Residual Formaldehyde Example content (ppm) 1682 2 567 3 1621 4 820 5 24 6 34 7 5 8 293

1. Cucurbituril and/or one or more derivatives thereof comprising lessthan 300 ppm formaldehyde.
 2. Cucurbituril and/or one or morederivatives thereof according to claim 1 comprising less than 200 ppmformaldehyde.
 3. A process for the preparation of cucurbituril and/orone or more derivatives thereof comprising mixing glycoluril with amethylene bridging agent, in the presence of an acid and in the absenceof any formaldehyde, or formaldehyde precursor, wherein the glycolurilis selected from the group consisting of unsubstituted glycoluril,alkoxy-methylated glycoluril, glycoluril derivatives, and mixturesthereof.
 4. The process according to claim 3, wherein the glycoluril,the methylene bridging agent and the acid are mixed simultaneously, orare mixed sequentially.
 5. The process according to claim 4, wherein thealkoxy-methylated glycoluril is selected from monoalkoxy-methylated,dialkoxy-methylated, trialkoxy-methylated, or a mixture thereof.
 6. Theprocess according to claim 3, wherein the methylene bridging agent is acompound of formula (IV):

wherein each X is independently selected from the group consisting of anelectronegative atom, oxygen, nitrogen, sulphur and phosphorus; R₁ andR₂ are each independently selected from hydrogen, an unsubstituted orsubstituted straight chain, branched or cyclic, saturated or unsaturatedhydrocarbon radical; and R represents hydrogen.
 7. The process accordingto claim 3, wherein the methylene bridging agent is one or more membersselected from the group consisting of a dialkoxymethane reagent,dimethoxymethane, diethoxymethane, dipropoxymethane(1-(propoxymethoxy)propane), diisopropoxymethane(2-(isopropoxymethoxy)propane), dibutoxymethane(1-(butoxymethoxy)butane), di(tert-butoxy)methane(2-methyl-2-{[(2-methyl-2-propanyl)oxy]methoxy}propane), and mixturesthereof.
 8. The process according to claim 3, wherein the methylenebridging agent is one or more members selected from the group consistingof an alkoxymethyl alkanesulphonate, methoxymethane methane sulphonate,methoxymethyl benzenesulphonate, methoxymethyl p-toluene sulphonate,benzyloxymethyl methanesulphonate, and mixtures thereof.
 9. A processfor the preparation of cucurbituril comprising reacting a fullyalkoxy-methylated glycoluril with unsubstituted glycoluril in thepresence of an acid, and in the absence of any formaldehyde, orformaldehyde precursor.
 10. The process according to claim 3, whereinthe acid is a heterogeneous acid or a homogeneous acid, wherein when theacid is a heterogeneous acid, the heterogeneous acid is on a solidsupport such as an acidic resin.
 11. The process according to claim 3,wherein the acid is selected from the group consisting of a mineralacid, an organic acid, sulfuric acid, nitric acid, hydrochloric acid,hydrobromic acid, hydroiodic acid, phosphoric acid, toluenesulphonicacid, and alkanesulphonic acid.
 12. The process according to claim 3,wherein the acid is methanesulphonic acid.
 13. The process according toclaim 3, wherein the acid is provided in excess.
 14. The processaccording to claim 3, wherein the process is carried out at atemperature greater than 40° C.
 15. The process according to claim 3,wherein the glycoluril, the methylene bridging agent, if present, andthe acid are reacted for up to 18 hours. 16-17. (canceled)
 18. Acomposition comprising cucurbituril and/or one or more derivativesthereof, the composition comprising no more than 300 ppm formaldehydeoriginating from the cucurbituril and/or one or more derivativesthereof.
 19. (canceled)